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Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA

Plasmodium falciparum causes malaria in humans with over 450,000 deaths annually. The asexual blood stage involves invasion of erythrocytes by merozoites, in which they grow and divide to release daughter merozoites, which in turn invade new erythrocytes perpetuating the cycle responsible for malari...

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Autores principales: Chen, Lin, Xu, Yibin, Wong, Wilson, Thompson, Jennifer K, Healer, Julie, Goddard-Borger, Ethan D, Lawrence, Michael C, Cowman, Alan F
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349848/
https://www.ncbi.nlm.nih.gov/pubmed/28195530
http://dx.doi.org/10.7554/eLife.21347
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author Chen, Lin
Xu, Yibin
Wong, Wilson
Thompson, Jennifer K
Healer, Julie
Goddard-Borger, Ethan D
Lawrence, Michael C
Cowman, Alan F
author_facet Chen, Lin
Xu, Yibin
Wong, Wilson
Thompson, Jennifer K
Healer, Julie
Goddard-Borger, Ethan D
Lawrence, Michael C
Cowman, Alan F
author_sort Chen, Lin
collection PubMed
description Plasmodium falciparum causes malaria in humans with over 450,000 deaths annually. The asexual blood stage involves invasion of erythrocytes by merozoites, in which they grow and divide to release daughter merozoites, which in turn invade new erythrocytes perpetuating the cycle responsible for malaria. A key step in merozoite invasion is the essential binding of PfRh5/CyRPA/PfRipr complex to basigin, a step linked to the formation of a pore between merozoites and erythrocytes. We show CyRPA interacts directly with PfRh5. An invasion inhibitory monoclonal antibody to CyRPA blocks binding of CyRPA to PfRh5 and complex formation thus illuminating the molecular mechanism for inhibition of parasite growth. We determined the crystal structures of CyRPA alone and in complex with an antibody Fab fragment. CyRPA has a six-bladed β-propeller fold, and we identify the region that interacts with PfRh5. This functionally conserved epitope is a potential target for vaccines against P. falciparum. DOI: http://dx.doi.org/10.7554/eLife.21347.001
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spelling pubmed-53498482017-03-15 Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA Chen, Lin Xu, Yibin Wong, Wilson Thompson, Jennifer K Healer, Julie Goddard-Borger, Ethan D Lawrence, Michael C Cowman, Alan F eLife Biochemistry Plasmodium falciparum causes malaria in humans with over 450,000 deaths annually. The asexual blood stage involves invasion of erythrocytes by merozoites, in which they grow and divide to release daughter merozoites, which in turn invade new erythrocytes perpetuating the cycle responsible for malaria. A key step in merozoite invasion is the essential binding of PfRh5/CyRPA/PfRipr complex to basigin, a step linked to the formation of a pore between merozoites and erythrocytes. We show CyRPA interacts directly with PfRh5. An invasion inhibitory monoclonal antibody to CyRPA blocks binding of CyRPA to PfRh5 and complex formation thus illuminating the molecular mechanism for inhibition of parasite growth. We determined the crystal structures of CyRPA alone and in complex with an antibody Fab fragment. CyRPA has a six-bladed β-propeller fold, and we identify the region that interacts with PfRh5. This functionally conserved epitope is a potential target for vaccines against P. falciparum. DOI: http://dx.doi.org/10.7554/eLife.21347.001 eLife Sciences Publications, Ltd 2017-02-14 /pmc/articles/PMC5349848/ /pubmed/28195530 http://dx.doi.org/10.7554/eLife.21347 Text en © 2017, Chen et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry
Chen, Lin
Xu, Yibin
Wong, Wilson
Thompson, Jennifer K
Healer, Julie
Goddard-Borger, Ethan D
Lawrence, Michael C
Cowman, Alan F
Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA
title Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA
title_full Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA
title_fullStr Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA
title_full_unstemmed Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA
title_short Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA
title_sort structural basis for inhibition of erythrocyte invasion by antibodies to plasmodium falciparum protein cyrpa
topic Biochemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349848/
https://www.ncbi.nlm.nih.gov/pubmed/28195530
http://dx.doi.org/10.7554/eLife.21347
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